Synthesis and DNA binding of CIS and TRANS-RuCl2 (DMSO)4

Author (Your Name)

Thomas Curran, Colby College

Date of Award

2002

Document Type

Honors Thesis (Open Access)

Department

Colby College. Chemistry Dept.

Advisor(s)

Shari U. Dunham

Abstract

The synthesis of both cis and trans-RuCl?(DMSO)? has been reported in literature, and is currently the only way of acquiring these compounds. Because these metallodrugs have shown similar antitumor properties to cisplatin, they are currently under investigation for use in clinical trials as potential chemotherapeutics. It is believed that these drugs act in a way similar to cisplatin by causing intrastrand crosslinking of adjacent guanine residues in DNA. In an attempt to better understand any Ru/DNA interaction for these compounds, both cis and trans-RuCl?(DMSO)? were synthesized with reasonable yields (~40%). The compounds were then characterized by nuclear magnetic resonance (NMR), combustion elemental analysis (CHN), and ultravioletvisible spectroscopy (UV -Vis). These compounds were then reacted in aqueous solution with various types of DNA (calf thymus, nucleosides, and a synthetic 11 base oligonucleotide). The products of these reactions were separated and collected using either two different types of high performance liquid chromatography (HPLC), ethanol precipitation, or centrifugation filtration. Collected products were then analyzed using inductively coupled plasma atomic emission spectroscopy (lCP-AES) and electrospray ionization mass spectrometry (ESI-MS). Reactions with calf thymus DNA proved very hard to work with and only allowed for some indications of the reaction kinetics. Focus was then directed towards nucleosides and the 11 base oligonucleotide. No Ru-bound DNA was seen using ESI-MS, but the HPLC traces did indicate some Ru/DNA interaction. HPLC data suggested that this interaction may be reversible over time. The solution chemistry of the compounds was examined and compared to previous reports. It was discovered that the presence of phosphate buffer in solution with cis-RuCl?(DMSO)? causes the formation of a ruthenium/phosphate dimer of proposed molecular formula Ru?PO?(DMSO)?(H?O)x. If this dimer is formed inside cells, it may be partially responsible for the lower antitumor activity of cis-RuCl?(DMSO)? compared to trans-RuCl?(DMSO)?.

Keywords

Ruthenium synthesis, Transition metal complexes synthesis, DNA-ligand interactions

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